Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia

David J. Rabbolini, Yenna Chun, Maya Latimer, Shinji Kunishima, Kathleen Fixter, Bhavia Valecha, Peter Tan, Lee Ping Chew, Benjamin T. Kile, Rachel Burt, Kottayam Radhakrishnan, Robert Bird, Paul Ockelford, Sara Gabrielli, Qiang Chen, William S. Stevenson, Christopher M. Ward, Marie Christine Morel-Kopp

Research output: Contribution to journalArticleResearchpeer-review

Abstract

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

Original languageEnglish
Pages (from-to)793-800
Number of pages8
JournalPlatelets
Volume29
Issue number8
DOIs
Publication statusPublished - 17 Nov 2018

Keywords

  • Inherited macrothrombocytopenia
  • MYH9
  • next generation sequencing
  • platelets
  • thrombopoietin agonists

Cite this

Rabbolini, D. J., Chun, Y., Latimer, M., Kunishima, S., Fixter, K., Valecha, B., ... Morel-Kopp, M. C. (2018). Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia. Platelets, 29(8), 793-800. https://doi.org/10.1080/09537104.2017.1356920
Rabbolini, David J. ; Chun, Yenna ; Latimer, Maya ; Kunishima, Shinji ; Fixter, Kathleen ; Valecha, Bhavia ; Tan, Peter ; Chew, Lee Ping ; Kile, Benjamin T. ; Burt, Rachel ; Radhakrishnan, Kottayam ; Bird, Robert ; Ockelford, Paul ; Gabrielli, Sara ; Chen, Qiang ; Stevenson, William S. ; Ward, Christopher M. ; Morel-Kopp, Marie Christine. / Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia. In: Platelets. 2018 ; Vol. 29, No. 8. pp. 793-800.
@article{2da7d26736184989ab9d9d260ff33960,
title = "Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia",
abstract = "MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (d{\"o}hle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4{\%}) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1{\%}), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91{\%} were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if d{\"o}hle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.",
keywords = "Inherited macrothrombocytopenia, MYH9, next generation sequencing, platelets, thrombopoietin agonists",
author = "Rabbolini, {David J.} and Yenna Chun and Maya Latimer and Shinji Kunishima and Kathleen Fixter and Bhavia Valecha and Peter Tan and Chew, {Lee Ping} and Kile, {Benjamin T.} and Rachel Burt and Kottayam Radhakrishnan and Robert Bird and Paul Ockelford and Sara Gabrielli and Qiang Chen and Stevenson, {William S.} and Ward, {Christopher M.} and Morel-Kopp, {Marie Christine}",
year = "2018",
month = "11",
day = "17",
doi = "10.1080/09537104.2017.1356920",
language = "English",
volume = "29",
pages = "793--800",
journal = "Platelets",
issn = "0953-7104",
publisher = "Taylor & Francis",
number = "8",

}

Rabbolini, DJ, Chun, Y, Latimer, M, Kunishima, S, Fixter, K, Valecha, B, Tan, P, Chew, LP, Kile, BT, Burt, R, Radhakrishnan, K, Bird, R, Ockelford, P, Gabrielli, S, Chen, Q, Stevenson, WS, Ward, CM & Morel-Kopp, MC 2018, 'Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia' Platelets, vol. 29, no. 8, pp. 793-800. https://doi.org/10.1080/09537104.2017.1356920

Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia. / Rabbolini, David J.; Chun, Yenna; Latimer, Maya; Kunishima, Shinji; Fixter, Kathleen; Valecha, Bhavia; Tan, Peter; Chew, Lee Ping; Kile, Benjamin T.; Burt, Rachel; Radhakrishnan, Kottayam; Bird, Robert; Ockelford, Paul; Gabrielli, Sara; Chen, Qiang; Stevenson, William S.; Ward, Christopher M.; Morel-Kopp, Marie Christine.

In: Platelets, Vol. 29, No. 8, 17.11.2018, p. 793-800.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia

AU - Rabbolini, David J.

AU - Chun, Yenna

AU - Latimer, Maya

AU - Kunishima, Shinji

AU - Fixter, Kathleen

AU - Valecha, Bhavia

AU - Tan, Peter

AU - Chew, Lee Ping

AU - Kile, Benjamin T.

AU - Burt, Rachel

AU - Radhakrishnan, Kottayam

AU - Bird, Robert

AU - Ockelford, Paul

AU - Gabrielli, Sara

AU - Chen, Qiang

AU - Stevenson, William S.

AU - Ward, Christopher M.

AU - Morel-Kopp, Marie Christine

PY - 2018/11/17

Y1 - 2018/11/17

N2 - MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

AB - MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

KW - Inherited macrothrombocytopenia

KW - MYH9

KW - next generation sequencing

KW - platelets

KW - thrombopoietin agonists

UR - http://www.scopus.com/inward/record.url?scp=85058243899&partnerID=8YFLogxK

U2 - 10.1080/09537104.2017.1356920

DO - 10.1080/09537104.2017.1356920

M3 - Article

VL - 29

SP - 793

EP - 800

JO - Platelets

JF - Platelets

SN - 0953-7104

IS - 8

ER -

Rabbolini DJ, Chun Y, Latimer M, Kunishima S, Fixter K, Valecha B et al. Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia. Platelets. 2018 Nov 17;29(8):793-800. https://doi.org/10.1080/09537104.2017.1356920